Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment.
Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment.
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正常上皮细胞的生存需要基质附着，而肿瘤细胞在其天然细胞外基质（ECM）微环境之外生存的能力取决于获得锚定非依赖性。虽然凋亡是清除缺乏适当ECM附着细胞的最快速机制，但最近的报道表明，当基质剥夺细胞中的凋亡受到抑制时，非凋亡性死亡过程会阻止细胞存活。在此我们证明，乳腺上皮细胞从ECM脱离会因葡萄糖转运缺失而导致ATP缺乏。ErbB2的过表达通过稳定表皮生长因子受体（EGFR）和激活磷脂酰肌醇 - 3 - 激酶（PI(3)K）恢复葡萄糖摄取，从而挽救ATP缺乏，并且这种挽救依赖于通过产生抗氧化剂的磷酸戊糖途径（PPP）的葡萄糖刺激通量。有趣的是，我们发现通过抗氧化处理可以挽救ATP缺乏，而无需挽救葡萄糖摄取。这种挽救被发现依赖于脂肪酸氧化（FAO）的刺激，而脂肪酸氧化会受到脱离诱导的活性氧（ROS）的抑制。这些发现的重要性得到了以下证据的支持：乳腺腺泡腔隙中基质剥夺细胞中的ROS升高，并且抗氧化剂促进这些细胞的存活并增强锚定非依赖性集落形成。这些结果既揭示了基质附着在调节代谢活动中的重要性，也揭示了在改变的基质环境中通过抗氧化恢复ATP生成实现细胞存活的一种意想不到的机制。
Normal epithelial cells require matrix attachment for survival and the ability of tumour cells to survive outside their natural extracellular matrix (ECM) niches is dependent on acquisition of anchorage independence. While apoptosis is the most rapid mechanism for eliminating cells lacking appropriate ECM attachment, recent reports suggest that non-apoptotic death processes prevent survival when apoptosis is inhibited in matrix-deprived cells. Here we demonstrate that detachment of mammary epithelial cells from ECM causes an ATP deficiency due to loss of glucose transport. Overexpression of ErbB2 rescues the ATP deficiency by restoring glucose uptake through stabilization of EGFR and PI(3)K activation and this rescue is dependent on glucose-stimulated flux through the antioxidant-generating pentose phosphate pathway (PPP). Interestingly, we found that the ATP deficiency could be rescued by antioxidant treatment without rescue of glucose uptake. This rescue was found to be dependent on stimulation of fatty acid oxidation (FAO), which is inhibited by detachment-induced reactive oxygen species (ROS). The significance of these findings was supported by evidence of an elevation in ROS in matrix-deprived cells in the luminal space of mammary acini and that antioxidants facilitate the survival of these cells and enhance anchorage-independent colony formation. These results reveal both the importance of matrix attachment in regulating metabolic activity and an unanticipated mechanism for cell survival in altered matrix environments through antioxidant restoration of ATP generation.
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